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Planning a Multi-Step Synthesis: Order, Protection and Yield

A route that works on paper can still fail in a flask. Order of steps, groups that need hiding, and the way yields multiply decide whether a plan is worth running.

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What a learner can do afterwards

  • Orders steps so that each reagent meets only the groups it tolerates
  • Inserts protection and deprotection where a reagent would otherwise attack the wrong site
  • Multiplies stage yields to get an overall figure and argues for a shorter route on that basis
  • Identifies the step most likely to fail on scale and proposes an alternative

1 · Read

You think in routes, not single reactions. Each reagent you pick must tolerate every other group present at that moment, so order decides success or failure. If you oxidise too early, a later Grignard will attack the carbonyl you just made, so you reorder the steps or mask the group first. You build fragile rings late so they survive the fewest steps.

When a later reagent would attack a group you want to keep, you mask it first, run the step, then reveal it. You hide an aldehyde as an acetal and restore it later with mild acid, or mask an alcohol as a silyl ether. Ethers work well as protection because they are famously unreactive.

Try it together

You multiply fractional yields to get your overall figure. Three stages at 80 percent give 0.8 times 0.8 times 0.8, about 51 percent. A ten step route at 80 percent per step delivers only about 11 percent overall, while a six step route at the same stage yield delivers 26 percent, so you argue for the shorter route. When a stage needs extreme cold, explosive reagents, or endless chromatography, you redesign around it rather than forcing it through.

Good to know

You isolate each stage by distillation or recrystallization before the next begins, since impurities carried forward can poison later steps.

You order steps to protect earlier work, hide reactive groups, multiply yields to favour short routes, and redesign risky steps.

2 · Watch

Take it off screen

Print a worksheetA4 with an answer key page for grown-ups. No screen, no internet.

Where it sits

Then practise

8 questions wait behind this lesson, each with its answer explained. Every answer feeds the sky: stars light as they are learned, and dim when it is time to come back.

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Planning a Multi-Step Synthesis: Order, Protection and Yield · Science, ages 21 to 22 · LightMySky